MXPA04009055A - Formulation comprising buprenorphine. - Google Patents

Abstract

Aqueous formulations suitable for intranasal administration comprise buprenorphine or a physiologically acceptable salt or ester thereof and (a) a pectin having a degree of esterification of less than 50%, (b) chitosan and a polyoxyethylene-polyoxypropylene copolymer (poloxamer) or (c) chitosan and hydroxypropylmethylcellulose. Such formulations can induce rapid and prolonged analgesia when delivered intranasally to a patient. The buprenorphine or buprenorphine salt or ester may be delivered to the bloodstream to produce within 30 minutes a therapeutic plasma concentration of buprenorphine, Cther, of 0.2 ng/ml or greater which is maintained for a duration Tmaint of at least 2 hours.

Description

befare ihe expired of ilw lime limit for ameruiin? ihe For G ?? - lelier coties and other abbrevi iions. refer w ihe "GuiJ- claims and ¡o be republisheú ui ¡he eve.nl of receipt of the Notes on Codes anJ Abbrevi ii ns" ppe rmg < it ihebes - rncTidmems. ninv f ih revuliir issue. of ¡he PCT (ti eue. (8X > Dale? G puhli uliun? G (lie inlcrnuUunal scurch rcport: 31 Detember: U03 FORMULATION COMPRISING BUPRENORPHINE Field of the Invention The invention relates to pharmaceutical formulations of buprenorphine and physiologically acceptable salts and esters thereof. Background of the Invention The term opioid (or opioid) defines drugs with properties similar to that of morphine. Opioids can be subclassified on the basis of their specificity by the receptor. Mu agonist opioids provide intense analgesia. These opioids can act for a long time (for example, methadone) or act briefly (for example, remifentanil). Mixed agonist / antagonist opioids (eg, butorphanol and buprenorphine) are partial agonists (the former at the mu and kappa receptors and the latter at the mu receptor) and can produce good quality analgesia. They produce less depression and respiratory constipation than highly effective mu agonists. Buprenorphine (CAS RN 52485-79-7; [5 -7a (S) -17- (Cyclopropylmethyl) -a- (1,1-dimethylethyl) -4,5-epoxy-18,19-dihydro-3-hydroxy -6-methoxy-a-methyl-6,14-etenomorfinan-7-methanol) has the formula: Ref: 158662 The hydrochloride is also active (CAS RN 53152-21-9). Buprenorphine is a highly lipophilic derivative of thebaine. This is a partial mu agonist and mediates analgesia in the mu opioid receptor. Buprenorphine produces a maximum analgesic effect similar to that of full mu agonists such as morphine in animal models of pain and, although it may have a maximum effect on certain types of pain in man, it has been shown to produce good quality analgesia of efficacy similar to that of morphine in most clinical situations including severe pain. An unusual property of buprenorphine observed in in vitro studies is its very slow rate of dissociation from its receptor. As a class, opioids are associated with numerous undesirable side effects, including respiratory depression, nausea, vomiting, dizziness, lack of mental clarity, dysphoria, pruritus, constipation, increased biliary tract pressure, urinary retention, and hypotension. The development of tolerance and the risk of 3 Chemical dependence and 'abuse are additional problems. However, it is unusual for buprenorphine to exhibit a low maximum effect of respiratory depression and also a bell-shaped dose response curve where the effect is first increased with larger doses, reaches a maximum and then decreases when the dose is increased. it increases even more, which makes it a safer drug than morphine, where respiratory depression will eventually lead to death. Buprenorphine has also been shown to have a lower incidence of other side effects such as constipation in men, and has a lower abuse potential than full mu agonists. Buprenorphine has been administered via the intravenous, intramuscular and sublingual routes to human subjects. There are limited reports of nasal administration. Eriksen et al, J. Pharm. Pharmacol. 41, 803-805, 1989 reports the administration to human volunteers of nasal spray. The spray consisted of 2 mg / ml of buprenorphine hydrochloride dissolved in 5% dextrose and the pH of the solution was adjusted to pH 5. WO 90/09870 describes a composition for administration to the mucosa comprising a pharmacologically active compound and a polycationic substance such as DEAE-dextran or chitosan. WO 98/47535 describes a single component liquid pharmaceutical composition for administration to a mucosal surface. The composition 4 it comprises a therapeutic agent, a pectin with a low degree of esterification and an aqueous carrier which gels or can be adapted to gel at the site of application. Neither WO 90/09780 nor WO 98/47535 mention buprenorphine. Summary of the Invention Improved formulations of buprenorphine have been devised for nasal administration. Rapid absorption of buprenorphine through the nasal mucosa into the plasma can be achieved, which results in rapid onset of analgesia. In addition, the residence time of buprenorphine in the nasal cavity can be increased, which results in prolonged analgesia. In this way, the absorption profile of buprenorphine in the systemic circulation can be improved by using the formulation. Accordingly, the present invention provides: (1) an aqueous solution suitable for intranasal administration, which comprises from 0.1 to 10 mg / ml of buprenorphine or a physiologically acceptable salt or ester thereof and from 5 to 40 mg / ml of a pectin having an esterification degree of less than 50%; solution which has a pH of from 3 to 4.2, is substantially free of divalent metal ions and gels on the nasal mucosa; (2) an aqueous solution suitable for intranasal administration, which comprises: (a) from 0.1 to 10 mg / ml of buprenorphine or a salt or ester physiologically acceptable thereof, (b) from 0.1 to 20 mg / ml of chitosan, and (c) from 0.1 to 15 mg / ml of hydroxypropylmethylcellulose (HPMC); solution which has a pH of 3 to 4.8; and (3) an aqueous solution suitable for intranasal administration, which comprises: (a) from 0.1 to 10 mg / ml of buprenorphine or a pharmaceutically acceptable salt or ester thereof, (b) from 0.1 to 20 mg / ml of a chitosan, and (c) from 50 to 200 mg / ml of a polyoxyethylene-polyoxypropylene copolymer of the general formula HO (C2H40.} A (C3H60) b (C2H40) aH where a is from 2 to 130 and b is from 15 to 67; solution which has a pH of 3 to 4.8. A preferred solution of the invention has a pH of 3.5 to 4.0, is substantially free of divalent metal ions and comprises: (a) from 1 to 6 mg / ml of buprenorphine or a pharmaceutically acceptable salt or ester thereof, calculated as buprenorphine; (b) from 10 to 40 mg / ml of a pectin having an esterification degree of 10 to 35%, and (c) dextrose as an agent for adjusting the tonicity. The invention also provides: 6 - a process for the preparation of. the solution (1), which comprises dissolving the buprenorphine or a physiologically acceptable salt or ester thereof in water; mix the remaining solution with a water solution of a pectin having an esterification degree of less than 50%, so that the mixed solution comprises 0.1 to 10 mg / ml of buprenorphine or the salt or ester thereof and of 5 to 40 mg / ml of pectin; and adjust the pH of the solution to a value of 3 to 4.2 if desired; - a process for the preparation of the solution (2), which comprises dissolving the buprenorphine or a physiologically acceptable salt or ester thereof, a chitosan and HPMC in water to provide a solution comprising 0.1 to 10 mg / ml of buprenorphine or the salt or ester thereof, from 0.1 to 20 mg / ml of chitosan and from 0.1 to 15 mg / ml of HPMC; and adjust the pH of the solution to a value of 3 to 4.8 when desired; - a process for the preparation of the solution (3), which comprises dissolving the buprenorphine or a physiologically acceptable salt or ester thereof, a chitosan and a polyoxyethylene-polyoxypropylene copolymer of the general formula HO (C2H40) to (C3H60) ) b (C2H40) aH where a is from 2 to 130 and b is from 15 to 67, in water to provide a solution comprising 0.1 to 10 mg / ml of buprenorphine or the salt or ester thereof, from 0.1 to 20 mg / ml of a chitosan and 50 to 200 mg / ml of the polyoxyethylene-polyoxypropylene copolymer; and 7 adjust the pH of the solution to a value of 3 to 4. 8 when desired, - - a nasal delivery device loaded with a solution of the invention; - the use of a solution of the invention for the manufacture of a nasal delivery device to be used to induce analgesia; - a method for inducing analgesia in a patient in need thereof, which method comprises administering intranasally a solution of the invention to the patient. The invention allows a therapeutic concentration in blood plasma of buprenorphine, ie a concentration of buprenorphine that produces pain relief or pain reduction, which is achieved within 30 minutes and is maintained for up to 24 hours. The term Cter denotes the therapeutic concentration in blood plasma. The term Tmant denotes the duration during which Cter is maintained. Additionally, therefore, the present invention provides the use of buprenorphine or a physiologically acceptable salt or ester thereof and a release agent for the manufacture of a medicament to be administered intranasally for the treatment of pain so, upon introduction in the nasal cavity of a patient to be treated, the buprenorphine or salt or ester thereof is taken to the bloodstream to produce inside the of 30 minutes a therapeutic concentration in plasma Cter of 0.2 ng / ml or greater which is administered during a. Tmant time of at least 2 hours. Also provided are: the use of a pharmaceutical composition which comprises buprenorphine or a physiologically acceptable salt or ester thereof and a release agent for the manufacture of a nasal delivery device to be used to induce analgesia so, upon introduction In the nasal cavity of a patient to be treated, the buprenorphine or salt or ester thereof is taken to the bloodstream to produce within 30 minutes a therapeutic concentration in Cter plasma of 0.2 ng / ml or greater, which is maintained for a time Tmant of at least 2 hours; - a pharmaceutical composition suitable for use as an analgesic which comprises buprenorphine or a physiologically acceptable salt or ester thereof and a release agent whereby, after introduction into the nasal cavity of a patient to be treated, buprenorphine or salt or ester thereof is brought into the bloodstream to produce within 30 minutes a therapeutic concentration in Cter plasma of 0.2 ng / ml or greater, which is maintained for a time of at least 2 hours; - a method to induce analgesia in a patient who needs it, a method which comprises administering intranasally to the patient a pharmaceutical composition which comprises buprenorphine or a physiologically acceptable salt or ester thereof and a release agent whereby, after introduction into the nasal cavity of the patient to be treated, the buprenorphine or salt or ester of the It is taken to the bloodstream to produce within 30 minutes a therapeutic concentration in Cter plasma of 0.2 ng / ml or greater which is maintained for a Tmant time of at least 2 hours. Brief Description of the Figures Figures 1 to 3 show the pharmacokinetic profiles that were obtained when formulations of buprenorphine according to the invention (Formulations A to C) were administered intranasally to healthy volunteers at a dose of 800 μg of buprenorphine hydrochloride, calculated as buprenorphine. Formulation A: buprenorphine-pectin hydrochloride solution. Formulation B: solution of buprenorphine hydrochloride-chitosan / hydroxypropylmethylcellulose (HPMC). Formulation C: buprenorphine-chitosan / poloxamer 188 hydrochloride solution. Also shown for comparison is the pharmacokinetic profile that was obtained when a commercial solution of buprenorphine hydrochloride (Temgesic - brand name, Formulation D) was administered intravenously to volunteers healthy in the same study at a dose of 400 g of buprenorphine hydrochloride, calculated as buprenorphine. 10 Figure 4 shows a pharmacokinetic profile for a 400 μ9 dose of Formulation A. This profile was calculated from the data for the 800 μ9 dose of Formulation A. The pharmacokinetic profile for the 400 μ9 dose of Formulation D also It is shown for comparison. Detailed Description of the Invention A first pharmaceutical solution of the invention consists essentially of 0.1 to 10 mg / ml of buprenorphine or a physiologically acceptable salt or ester thereof, of 5 to 40 mg / ml of a pectin having a low degree of esterification, in particular a degree of esterification of less than 50%, and water. The buprenorphine salt can be an acid addition salt or a salt with a base. Suitable acid addition salts include hydrochloride, sulfate, methane sulfonate, stearate, tartrate and lactate salts. The hydrochloride salt is preferred. The concentration of buprenorphine or buprenorphine salt or ester is 0.1 to 10 mg / ml, for example 0.5 to 8 mg / ml. Preferred concentrations are from 1 to 6 mg / ml, for example from 1 to 4 mg / ml calculated as buprenorphine. Suitable solutions may contain buprenorphine or a salt or ester of buprenorphine in an amount of 1 mg / ml or 4 mg / ml, calculated as buprenorphine. The solution is typically provided as a nasal spray. A spray of 100 μ? of a solution that contains 1 to 11 4 mg / ml of buprenorphine or a buprenorphine salt or ester, calculated as buprenorphine thus results in a clinical dose of 100 to 400 μg of buprenorphine or buprenorphine salt or ester, calculated as buprenorphine. Two of those window sprays can be given per administration time to provide a dose of up to 4 x 400 ie up to 1600 μg / of buprenorphine or buprenorphine salt or ester, calculated as buprenorphine. Pectin is a gelling agent. The solution of the invention gels on the mucous surfaces of the nasal cavity after its release without the need for a foreign source of divalent metal ions. The buprenorphine or salt or ester of buprenorphine that is formulated with pectin is thus retained for a longer time on the surfaces of the nasal epithelium. The resulting sustained release of buprenorphine or buprenorphine salt or ester into the blood stream allows prolonged analgesia to be achieved. Accordingly, an improved release of buprenorphine or a salt or ester of buprenorphine can be obtained. Rapid absorption of buprenorphine or buprenorphine salt or ester also results, which leads to a rapid onset of analgesia. The solutions of the invention contain a pectin having an esterification degree of less than 50%. A pectin is a polysaccharide substance present in walls 12 Cells of all plant tissues. Commercial pectins are usually obtained from the diluted acidic extract of the inner portion of the citrus fruit peel or the apple pulp. A pectin contains partially methoxylated polygalacturonic acids. The proportion of galacturonic acid entities in the form of methyl ester represents the degree of esterification (GE). The term GE is well understood by those skilled in the art and can be presented as the percentage of total number of carboxyl groups that are esterified, ie four of five acid groups are esterified this represents an 80% degree of esterification, or as the methoxyl content of pectin. GE as used herein refers to the total percentage of carboxyl groups that are esterified. Pectins can be classified into categories in those that have a low degree of esterification (low methoxylation) or a high degree of esterification (high methoxylation). A "low GE" or "DM" pectin has an esterification degree of less than 50% while a "high GE" or "AM" pectin has an esterification degree of 50% or higher. The gelling properties of the aqueous pectin solutions can be controlled by the concentration of pectin, the type of pectin, especially the degree of esterification of the galacturonic acid units, and the presence of added salts. 13 Low GE pectins are used in the present invention The main mechanism by which these pectins gel in aqueous solution is through exposure to metal ions, such as those found in the nasal mucosal fluid as described in WO. The degree of esterification of the pectin used in the invention is preferably less than 35% The degree of esterification can thus be from 10 to 35%, for example from 15 to 25%. low GE can be purchased commercially An example of a low GE pectin is the SLE DID (trademark) 100, distributed by CP Kelco (Lille Skenved) which has an esterification degree of approximately 15 to 25%. The pectin-containing composition of the invention should not gel during storage It should not gel prior to application to the nasal cavity, therefore it should be substantially free of agents that could cause the solution to gel. In particular, a solution of the invention should be substantially free of divalent metal ions and especially calcium ions. The content of divalent metal ions in the solution must therefore be decreased. A solution of the invention can therefore contain a negligible concentration of divalent metal ions or must not have detectable divalent metal ions. 14 A pectin is present in the solution of the invention at a concentration of 5 to 40 mg / ml, for example 5 to 30 mg / ml. More preferably, the concentration of pectin is from 10 to 30 mg / ml or from 10 to 25 mg / ml. The pectin and the pectin concentration are selected so that the solution gels as it is delivered to the nasal mucosa. The solution gels on the nasal mucosa in the absence of an external source of divalent metal ions, for example Ca 2+ ions. A pectin-containing solution of the invention has a pH of from 3 to 4.2. Any pH within this range can be used provided that the buprenorphine or buprenorphine salt or ester remains dissolved in the solution. The pH can be from 3.2 to 4.0, for example from 3.5 to 4.0. A particularly suitable pH of 3.6 to 3.8. The pH can be adjusted to an appropriate value by the addition of a physiologically acceptable acid and / or physiologically acceptable buffer. The pH can thus be adjusted only by means of a physiologically acceptable mineral acid or only by means of a physiologically acceptable organic acid. The use of hydrochloric acid is preferred. Any suitable preservative may be present in the solution, in particular a preservative that prevents microbial contamination of the solution. The preservative can be any pharmaceutically acceptable preservative, by 15 example . phenylethyl alcohol or propyl hydroxybenzoate (propylparaben) or one of its salts. Phenylethyl alcohol and propylparaben or propylparaben salt are preferably used in combination. The preservative must be compatible with the other components of the solution and, in particular, must not cause gelation of the solution. The solutions may include an agent for adjusting the tonicity such as a sugar, for example dextrose, or a polyhydric alcohol, for example mannitol. A solution can be hypertonic, substantially isotonic or hypotonic. A substantially isotonic solution can have an osmolality of 0.28 to 0.32 osmol / kg. An exactly isotonic solution is 0.29 osmol / kg. The osmolality of the solution can be from 0.1 to 0.8 osmol / kg, such as from 0.2 to 0.6 osmol / kg or preferably from 0.3 to 0.5 osmol / kg. Therefore, a sufficient amount of an agent to adjust the tonicity, such as dextrose or mannitol, can be present to achieve those osmolalities. Preferably a solution contains 50 mg / ml dextrose or mannitol. A pectin-containing solution of the invention is prepared by dissolving buprenorphine or a physiologically acceptable salt or ester thereof in water, typically Water for Injections, and the resulting solution is mixed with a solution of a suitable pectin in water, again typically Water. for Injections. The amount of buprenorphine 16 or salt thereof and pectin are selected so that they are dissolved from 0.1 to 10 mg / ml of buprenorphine or salt or ester of buprenorphine and from 5 to 40 mg / ml of pectin in the mixed solution. A conservative or combination of preservatives can be dissolved in the solution. The pH of the mixed solution can be adjusted to a value within the range of 3 to 4.2 as required. Preferably, the pH is adjusted with hydrochloric acid if adjustment of the pH is required. Other components in solution can be provided at any convenient stage. For example, dextrose or mannitol can be dissolved in the water in which the buprenorphine or buprenorine salt or ester is being dissolved. A sterile solution can be obtained using sterile starting materials and operating under sterile conditions and / or using standard sterilization techniques such as passing the final solution through a sterilizing filter. In this way a pyrogen-free solution can be provided. The solution can be introduced into a nasal delivery device, typically a sterile device. If required, before sealing the device, the solution can be protected with an inert gas such as nitrogen to protect it against oxidation. · A second solution of the invention consists essentially of 0.1 to 10 mg / ml of buprenorphine or a salt or physiologically acceptable ester thereof, 0.1 to 20 mg / ml of a chitosan, 0.1 to 15 mg / ml of HPMC, and water. A third solution of the invention consists essentially of 0.1 to 10 mg / ml of buprenorphine or a physiologically acceptable salt or ester thereof, 0.1 to 20 mg / ml of chitosan, 50 to 200 mg / ml of a polyoxyethylene copolymer -polyoxypropylene of the general formula HO (C2H40) to (C3H60) b (C2H40) aH wherein a is from 2 to 130 and b is from 15 to 67, and water. In each case, the buprenorphine salt can be an acid addition salt or a salt with a base. Suitable acid addition salts are as mentioned above. They include the salts of hydrochloride, sulfate, methane sulfonate, stearate, tartrate and lactate. The hydrochloride salt is preferred. The concentration of buprenorphine or buprenorphine salt or ester in any solution is 0.1 to 10 mg / ml, for example 0.5 to 8 mg / ml. Preferred concentrations are from 1 to 6 mg / ml, for example from 1 to 4 mg / ml. Suitable solutions may contain buprenorphine or buprenorphine salt or ester at a concentration of 1 mg / ml to 4 mg / ml, calculated as buprenorphine. Each solution is typically provided as a nasal spray. A spray of 100 μ? of a solution containing 1 to 4 mg / ml of buprenorphine or a salt or ester of buprenorphine, calculated as buprenorphine, thus results in a clinical dose of 100 to 400 μ of buprenorphine or salt or 'buprenorphine ester, calculated as buprenorphine. Two of these window sprays can be given per administration time to provide a dose of up to 4 x 400, that is up to 1600 μg of buprenorphine or buprenorphine salt or ester, calculated as buprenorphine. A chitosan is present in both solutions. Chitosan are cationic polymers that have mucoadhesive properties. Mucoadhesion is through the result of an interaction between the positively charged chitosan molecule and the negatively charged sialic acid or mucin groups (Soane et al, Int. J. Pharm 178, 55-65, 1999). 'The term' chitosan 'includes all derivatives of chitin, or poly-N-acetyl-D-glucosamine, including all polyglucosamines and oligomers of glucosamine materials of different molecular weights, in which the largest proportion of N-acetyl groups have been removed through hydrolysis (deacetylation). Preferably, the chitosan is produced from chitin by deacetylation to a degree of more than 40%, preferably between 50 and 98%, more preferably between 70% and 90%. Chitosan typically has a molecular weight of 4,000 Da or more, preferably 10,000 to 1,000,000 Da, more preferably 15,000 to 750,000 Da and more preferably 50,000 to 500,000 Da. 19 Chitosan can thus be a deacetylated chitin. This can be a physiologically acceptable salt. Suitable physiologically acceptable salts include salts with a pharmaceutically acceptable mineral or organic acid such as the nitrate, phosphate, lactate, citrate, hydrochloride and acetate salts. Preferred salts are chitosan glutamate and chitosan hydrochloride. Chitosan can be a derivative of a deacetylated chitin. Suitable derivatives include, but are not limited to, ester, ether or other derivatives formed by linking acyl and / or alkyl groups with the hydroxy groups, but not the amino groups, of a deacetylated chitin. Examples are 0- (Ci-6 alkyl) deacetylated chitin ethers and 0-acyl esters of deacetylated chitin. The derivatives also include modified forms of a deacetylated chitin for example a deacetylated chitin conjugated with polyethylene glycol. Low and medium viscosity chitosan suitable for use in the present invention can be obtained from several sources, including FMC Biopolymer, Drammen, Norway; Seigagaku America Inc., MD; USA; Meron (India) Pvt, Ltd., India; Vanson Ltd, VA, USA; and AMS Biotechnology Ltd., UK. Suitable derivatives include those that are described in Roberts, Chitan Chemistry, MacMillan Press Ltd., London 20 (1992). Particularly preferred chitosan compounds that may be mentioned include "Protosan" (trademark) available from FMC Biopolymer, Drammen, Norway. Chitosan is preferably soluble in water. An aqueous solution of chitosan can be prepared by dissolving chitosan base or a chitosan base derivative in a pharmaceutically acceptable mineral or organic acid such as hydrochloric, lactic, citric or glutamic acid or by dissolving a chitosan salt in water. Chitosan is present in solution at a concentration of 0.1 to 20 mg / ml, for example 0.5 to 20 mg / mol. Preferably the solution contains from 1 to 15 mg / ml, more preferably from 2 to 10 mg / ml, of chitosan. A concentration of chitosan of 5 mg / ml is particularly suitable. Any hydroxypropyl methylcellulose (HPMC) can be employed. Several grades of HPMC are available. For example, Dow Chemical Company produces a range of HPMC polymers under the trademark Methocel. The grade and concentration of HPMC are chosen so that the solution of the invention preferably has a viscosity, at 25 ° C as measured by a cone and plate viscometer (for example Brookfield), in the range of 1 to 200 cps, of preferable way from 3 to 150 cps and, more preferably, from 5 to 100 cps. twenty-one The production of a solution having a particular viscosity within the capacity of one skilled in the art and can be achieved, for example, by using a high concentration of a low viscosity HPMC or a low concentration of high viscosity HPMC. The HPMC used in the solution of the invention is preferably one having an apparent viscosity (measured as a 2% solution in water at 20 ° C) in the range of 3000 to 6000 cps. The concentration of HPMC having a viscosity of 3000 to 6000 cps is in the range of 0.1 to 15 mg / ml, preferably 0.5 to 10 mg / ml and preferably 1 to 5 mg / ml. The polyoxyethylene-polyoxypropylene copolymer typically has a molecular weight of 2500 to 18000, for example 7000 to 15000. The copolymer is a block copolymer of the general formula HO (C2H40) to (C3H60) b (C2H40) aH where a it is from 2 to 130 and b is from 15 to 67. The value for a can be from 40 to 100, such as from 60 to 90 or from 70 to 95. The value of b can be from 20 to 40, as from 25 to 35 Those copolymers are known as poloxamers. Several different types of poloxamers are commercially available, from distributors. as BASF, and vary with respect to the molecular weight and proportions of "a" units of ethylene oxide and "b" units of propylene oxide. A commercially available poloxamer suitable for use in the present invention is poloxamer 188 which structurally contains 80"a" units and 27"b" units and has a molecular weight of 7680-9510 (Handbook of Pharmaceutical Excipients, AH Kippe editor, third edition, Pharmaceutical Press, London , UK, 2000). Preferably the poloxamer is poloxamer 188. When the solution contains a poloxamer, the poloxamer is present at a concentration in the range of 50 to 200 mg / ml, preferably 65 to 160 mg / ml and more preferably 80 to 120. mg / ml. A preferred concentration is 100 mg / ml. Any suitable preservative may be present in the solution, in particular a preservative that prevents microbiological contamination of the solution. The conservator must be compatible with the other components of the solution. He . The preservative can be any pharmaceutically acceptable preservative, for example a quaternary ammonium compound such as benzalkonium chloride. The solution has a pH of 3 to 4.8. Any pH within this range can be used provided that the buprenorphine or buprenorphine salt or ester remains dissolved in the solution. The pH can be from 3.2 to 4.2, for example from 3.2 to 4.0 or 3.5 to 4.0. A particularly suitable pH is from 3.6 to 3.8. The pH can be adjusted to an appropriate value by the addition of a physiologically acceptable acid and / orphysiologically acceptable cushion. The pH can only be adjusted by means of a physiologically acceptable mineral acid or only by means of a physiologically acceptable organic acid. The use of hydrochloric acid is preferred. An agent can be included to adjust the tonicity in the solution. The agent for adjusting the tonicity can be a sugar, for example dextrose, or a polyhydric alcohol, for example mannitol. A solution can be hypertonic, substantially isotonic or hypotonic. Therefore, a sufficient amount of an agent to adjust the tonicity such as dextrose or mannitol may be present to achieve the desired osmolality. Preferably a solution contains 50 mg / ml dextrose or mannitol. The osmolality of a solution containing chitosan and HPMC or a poloxamer can be from 0.1 to 0.8 osmole / kg, from 0.2 to 6.0 osmole / kg or, preferably, from 0.32 to 0.4 osmole / kg.

The solutions may also contain other ingredients such as an antioxidant, chelating agent or other agent generally used in liquid pharmaceutical preparations. The solution can be a sterile solution. The solution containing chitosan and HPMC is prepared by dissolving buprenorphine or a physiologically acceptable salt or ester thereof, a chitosan and HPMC in water, typically Water for Injections. The amount of buprenorphine or salt or 24 Ester thereof is selected so that 0.1 to 10 mg / ml of buprenorphine or buprenorphine salt or ester are dissolved in the solution.The required concentrations of chitosan and HPMC are also provided.Conservator can be dissolved in the solution The pH of the solution can be adjusted to a value within the range of 3 to 4.8 when required.Preferably the pH is adjusted by means of hydrochloric acid.A solution containing chitosan and a polyoxyethylene-polyoxypropylene copolymer is prepared by dissolving buprenorphine. or a physiologically acceptable salt or ester thereof, a chitosan and the polyoxyethylene-polyoxypropylene copolymer in water, typically Water for Injections The amount of buprenorphine or salt or ester thereof is selected so as to dissolve from 0.1 to 10. mg / ml of buprenorphine or buprenorphine salt or ester in the solution.The required concentrations of chitosan and copolymer are provided. polyoxyethylene-polyoxypropylene. A preservative can be dissolved in the solution. The pH of the solution can be adjusted to a value within the range of 3 to 4.8 when required. Preferably, the pH is adjusted by means of hydrochloric acid. Other components in the solutions can be provided at any convenient stage. For example, dextrose or mannitol can be dissolved in water in which Buprenorphine or buprenorphine salt or ester is being dissolved. A sterile solution can be obtained using sterile starting materials and operating under sterile conditions and / or using standard sterilization techniques such as passing the final solution through a sterile filter. In this way it can provide a pyrogen-free solution. The solution can then be introduced into the nasal delivery device, typically a sterile device. If required, before sealing the device, the solution can be added with an inert gas such as nitrogen to protect it against oxidation. Each of the three solutions of the invention are administered intranasally to a patient, to induce analgesia. In this way, rapid onset of analgesia and prolonged analgesia can be obtained. An effective amount of buprenorphine or a salt or ester thereof is provided to the patient. A unit dose can be provided to a window. Alternatively, half a dose or two doses may be provided to each window each time of administration. The dose will depend on a number of factors including the age and sex of the patient, the nature and degree of the pain to be treated and the period of treatment. An adequate dose of buprenorphine or buprenorphine salt or ester is 0.02 to 1.2 mg, as of 50 to 26 600 μ9 or 100 to 400 μg, calculated as buprenorphine. Multiple doses of a solution according to the invention can be employed. For example, the rapid onset of analgesia produced by the solution of the invention may allow self-titration of analgesia by the patient. The analgesic effect of an initial dose can be calibrated quickly and reliably by the patient and, if insufficient, it can be supplemented immediately by additional doses (frequently alternating between each window) until the required level of analgesia is reached. Multiple doses can also be used to extend pain relief. For example, 2 to 4 doses per day may be indicated. The solutions of the invention can be used to treat an existing pain condition or to prevent a pain condition. An existing pain can be alleviated. The solutions of the invention can be used to treat or manage chronic or acute pain, for example the management of postoperative pain (for example, abdominal surgery, back surgery, cesarean section, hip replacement or knee replacement). Other medical uses include: preoperative intranasal administration of the solution of the invention; therapy or joint prophylaxis with anesthesia; postoperative analgesia; the 27th trauma pain management; the management of cancer pain; the management of endometriosis; the management of inflammatory pain; the management of arthritic pain (including the pain associated with rheumatoid arthritis and osteoarthritis); the management of back pain or low back pain; the management of myocardial pain (for example, ischemic or infarction pain); the management of dental pain; the management of neuropathic pain (for example, diabetic neuropathy, post-herpetic neuralgia or trigeminal neuralgia); the management of colic (for example colics or kidney stones), headaches, migraine, fibromyalgia or dysmenorrhea; the management of disabling pain associated with malignant and non-malignant diseases; and the management of acute procedural pain (for example, bone marrow aspiration or lumbar puncture). The solutions according to the invention can be administered to the nasal cavity in forms including drops or sprays. The preferred method of administration is to use a spray device. The spray devices may be of a single dose (unit) or multiple dose systems, for example comprising a bottle, pump and actuator. Suitable spray devices are available from various commercial sources including Pfeiffer, Valois, Bespak and Becton-Dickinson. As already mentioned, the rapid onset of analgesia and prolonged analgesia can be achieved by means of the invention. The analgesic release profile that can be achieved can avoid the relatively high Cmax values associated with intravenous administration and also lead to an improved therapeutic index.The peak plasma concentration of an analgesic that is reached after administration is defined. such as Cmax The invention may allow the reduction or elimination of some or all of the side effects associated with the analgesic Cmax is typically 1 to 5 ng / ml, for example 1 to 4 ng / ml or 1.5 to 3 ng Cmax can be 1 to 2 ng / ml, especially for lower doses of buprenorphine The time at which Cmax (Tmax) is reached is typically 10 to 40 minutes after administration, for example 10 to 30 minutes or 15 to 25 minutes, such as 15 to 20 minutes.In preferred embodiments, the release agent is adapted to release the analgesic component so that Cmax Copt.The term Copt is used in relation to analgesic drugs that exhibit a dose-response curve to analgesia that is displaced to the left with respect to the dose-response curve for side effects. The term defines a plasma therapeutic concentration, or range thereof, that produces acceptable pain relief or pain relief but that does not produce side effects or produces side effects which are less than those associated with high plasma concentrations. 29 Preferably, the solution of the invention allows the buprenorphine or salt or ester thereof to be delivered proportionate so that a Cter of 0.2 ng / ml or more, for example 0.4 ng / ml or more, is reached within 30 minutes (for example, within 0.5 to 20 minutes, such as 2 to 15 minutes or 5 to 10 minutes) after introduction into the nasal cavity. The term Cter defines a therapeutic concentration in plasma or interval thereof. Thus the term is used herein to define a concentration of a blood plasma (or range of plasma concentrations) of the buprenorphine or salt or ester thereof which produces pain relief or pain reduction. The Cter can be 0.4 to 5 ng / ml, for example 0.4 to 1 ng / ml or 0.5 to 4 ng / ml or 0.8 to 2 ng / ml. The Tmant is typically at least 2 hours. The term Tmant defines the duration of maintenance of the Cter after the administration of the analgesic. For example, the Tmant can be up to 24 hours, 12 hours or up to 6 hours, such as 2 to 4 or 2 to 3 hours. By means of the invention, therefore, a Cter of 0.4 ng / ml can be achieved within 2 to 15 minutes and maintained for a period of time Tmant of 2 to 4 hours. A further aspect of the invention relates to the pharmacokinetic profile that can be achieved. By using the solutions of the invention, not only can a rapid onset of analgesia be achieved, but it can also be achieved. be as a result prolonged analgesia. More generally, therefore, buprenorphine or buprenorphine salt or ester can be combined with a release agent in an intranasal formulation so that, after introduction into the nasal cavity of a patient to be treated, buprenorphine or salt or ester thereof is taken to the bloodstream to produce within 30 minutes a therapeutic concentration in Cter plasma of 0.2 ng / ml or greater that is maintained for a Tmant time of at least 2 hours. Buprenorphine is thus provided in a formulation suitable for nasal administration in combination with a release agent. The formulation is typically a liquid formulation, especially an aqueous solution. Alternatively, the formulation may be in the form of. a powder or microspheres. The buprenorphine salt can be an acid addition salt or a salt with a base. Suitable acid addition salts include the hydrochloride, sulfate, methanesulfonate, stearate, tartrate and lactate salts. The hydrochloride salt is preferred. When the formulation is a liquid formulation, the concentration of buprenorphine or buprenorphine salt or ester is 0.1 to 10 mg / ml, for example 0.5 to 8 mg / ml. Preferred concentrations are from 1 to 6 mg / ml, for example from 1 to 4 mg / ml calculated as buprenorphine. Suitable formulations may contain buprenorphine or a salt or ester of buprenorphine in an amount of 1 mg / ml or. 4 mg / ml, calculated as buprenorphine. The release agent is selected so that a rapid and prolonged onset analgesia is obtained. The release agent acts to release or carry the buprenorphine or buprenorphine salt or ester into the blood stream. Thus, the release agent acts as a modifier of the analgesic absorption and any of a wide variety of release agents can be used as long as this functional requirement is met. The release agent may comprise an absorption promoting agent. These agents promote the absorption of the analgesic component into the bloodstream. They can act via a variety of different mechanisms. Particularly preferred are mucosal adhesives. These adhesives maintain an intimate association between the bulk analgesic composition and the nasal mucosa, to improve absorption and extend the Tmant of the analgesic component. They can also be used to decrease analgesic Cmax, which may be important in applications where minimization or elimination of side effects is desired. Suitable absorption promoting agents include cationic polymers (particularly chitosan), surfactants, fatty acids, chelating agents, agents. mucolytics, "cyclodextrins, diethylaminoethyl dextran (DEAE-dextran, a polycationic derivative of dextran) or combinations thereof Particularly preferred are pectins which, as described above, have a degree of esterification of less than 50%, especially of 10 to 35%, and chitosanos, also as described above.

Other cationic polymers in addition to the chitosan suitable for use as absorption promoting agents include polycationic carbohydrates. The polycationic substances preferably have a molecular weight of at least 10000. They may be in liquid formulations at concentrations of 0.01 to 50% w / v, preferably from 0.1 to 50% w / v and more preferably 0.2 to 30% w / v v. Examples of suitable polycationic polymers are polyamino acids (e.g. polylysine), polyquaternary compounds, protamine, polyamine, DEAE-imine, polyvinylpyridine, polythiodiethyl-aminoethylene, polyhistidine, DEAE-methacrylate, DEAE-acrylamide, poly-p-aminostyrene, polyoxetane, copolymethacrylates. (for example copolymers of HPMA, N- (2-hydroxypropyl) -methacrylamide), GAFQUAT (see for example US 3,910,862) and polyamidoamines. Suitable surfactants for use in accordance with the present invention are bile salts (eg, sodium deoxycholate and colilsarcosine, a synthetic N-acyl conjugate of cholic acid with sarcosine [N-33]). methylglycine]). Also suitable for use in the invention are bile salt derivatives (eg tauro dihydrofusidate sodium). Any of a wide range of nonionic surfactants (e.g., polyoxyethylene-9-lauryl ether), phospholipids, and lysophosphatidyl compounds (e.g., lysolecithin, lysophosphatidylethanolamine, lysophosphatidylcholine, lysophosphatidylglycerol, lysophosphatidylserine, and lysophosphatidic acid) may also be used. Water-soluble phospholipids (for example phosphatidylglycerol and short-chain phosphatidylcholines) can also be used. The concentration of surfactants used according to the invention varies according to the physicochemical properties of the selected surfactants, but typical concentrations are in the range of 0.02 to 10% w / v. Particularly preferred surfactants for use as absorption promoting materials are phospholipids and lysophosphatides (product of phospholipid hydrolysis), both of which form micellar structures. When microspheres are used as a release agent, they are preferably prepared from a biocompatible material that will gel upon contact with the mucosal surface. The substantially uniform solid microspheres are preferred. The microspheres of 34 are preferred starch (crosslinked if necessary). The microspheres can also be prepared from starch derivatives, modified starches (such as amylodextrin), gelatin, albumin, collagen, dextran and dextran derivatives, polyvinyl alcohol, polylactide-co-glycolide, hyaluronic acid and derivatives thereof ( such as benzyl and ethyl esters), gellan gum and derivatives thereof (such as benzyl and ethyl esters) and pectin and derivatives thereof (such as benzyl and ethyl esters). The term "derivative" covers inter alia esters and ethers of the original compounds, which can be functionalized (for example to incorporate ionic groups). A wide variety of commercially available starch derivatives can be used, including hydroxyethyl starch, hydroxypropyl starch, carboxymethyl starch, cationic starch, acetylated starch, phosphorylated starch, starch succinate derivatives and grafted starches. Suitable dextran derivatives include, diethylaminoethyl-dextran (DEAE-dextran), dextran sulfate, dextran methyl-benzylamide sulfonates, dextran methyl-benzylamide carboxylates, carboxymethyl dextran, dextran diphosphonate, dextran hydrazide, palmitoyldextran and dextran phosphate. The preparation of microspheres for use according to the invention can be carried out by known processes, including emulsion and phase separation methods (see for example Davis et al., (Eds), "Microspheres and Drug Therapy", Elsevier Biomedical Press, 1984, of which the parts related to the preparation of microspheres are incorporated herein by reference ). For example, albumin microspheres can be produced using the water-in-oil emulsification method where the dispersion of albumin in oil is produced by homogenization or stirring, with addition, if necessary, of small amounts of an appropriate surfactant. The size of the microspheres is determined to a large extent by the agitation speed or the homogenization conditions. Agitation can be provided by a simple laboratory stirrer or by more sophisticated devices (such as microfluidizers or homogenizers). Emulsification techniques can also be used to produce microspheres (as described in GB 1518121 and EP 223303) and for the preparation of gelatin microspheres. The proteinaceous microspheres can be prepared by coacervation methods. These methods include simple or complex coacervation, as well as phase separation techniques (using solvents or electrolyte solutions). These methods are well known to those skilled in the art and details can be found in standard textbooks (eg Florence and Attwood, Physicochemical Principles of 36 Pharmacy.2da Ed., MacMillan Press, 1988, Chapter 8). The microspheres can advantageously have controlled release properties, which can be conferred by modifications of the microspheres (for example by controlling the degree of crosslinking or by incorporating excipients that alter the diffusion properties of the analgesic component). Alternatively, the controlled release properties can be incorporated by exploiting the ion exchange chemistry (for example DEAE-dextran and chitosan are positively charged and can be used for an ion exchange interaction with metabolites that are negatively charged. The maximum amount of analgesic component that can be carried by the microspheres is the so-called load capacity, which is determined by the physicochemical properties of the analgesic component and in particular its size and affinity for the microsphere matrix. the analgesic is incorporated into the microspheres during the manufacture of the microsphere.

Microcapsules (which may be bioadhesive and which may also exhibit controlled release properties) may also be employed as a promoter of the absorption of the compositions of the invention. These microcapsules can be produced by a variety of methods. The surface of the capsule may be inherently adhesive or may be modified by standard coating methods known to those skilled in the art. Suitable coating materials include bioadhesive polymers such as polycarbophil, carbopol, DEAE-dextran, alginate, microcrystalline cellulose, dextran, polycarbophiles and chitosan). The oil-in-water formulations can provide effective nasal release of analgesics that are poorly soluble in water. Nasal irritation can also be reduced in these applications. The oil phase of the emulsions of the invention may comprise a hydroxylated oil, particularly a hydroxylated vegetable oil. As used herein, the term "hydroxylated oil" is intended to cover any oil containing hydroxylated fatty acids. The preferred hydroxylated oils are hydroxylated vegetable oils, and a preferred hydroxylated vegetable oil for use in the present composition is castor oil. As used herein, the term "castor oil" is intended to include castor oil, Christie palm oil, tangantargon oil and Neoloide (as described in Merck Index, 12th Edition, p.311), as well as oil of Ricinus Zanzibarinus. The latter has a high glyceride content of ricinoleic acid. In this way, the oil of 38 ricino includes glycerides of ricinoleic acid (a hydroxy fatty acid). When castor oil is used in the present invention, it can be obtained, conveniently, by cold pressing of the seed of Ricinus Communis L. (family: Euphorbiaceae). The oil phase in the emulsions of the invention can constitute from 1 to 50% v / v of the emulsion. A preferred concentration of the preferred emulsion oil is 10 to 40% v / v. Particularly preferred are concentrations of 20 to 30% v / v. The emulsion compositions of the invention can be prepared using conventional methods such as the homogenization of a mixture of oil and analgesic component with an aqueous phase (optionally together with a stabilizing agent). Any suitable device can be used, including a microfluidizer or ultrasonic device, although microfluidizers are preferred for large-scale production. Suitable stabilizers for use in the emulsions of the invention include block copolymers containing a polyoxyethylene block (ie, a block consisting of repeating ethylene oxide entities). An example of a suitable stabilizer of this type is the Poloxamer. "Other suitable stabilizers include 39 phospholipid emulsifiers (for example, soybean and egg lecithin). Particularly preferred is the egg lecithin Lipoid? D? "11 (from Lipoid"), which contains phosphatidylcholine and phosphatidyl ethanolin. Other suitable phospholipids include the phospholipid-polyethylene glycol (PEG) conjugates (see for example Litzinger et al., Biochem Biophys Acta, 1190 (1994) 99-107). Any suitable concentration of stabilizer / emulsifier can be used, and it specifically falls within the range of 0.1 to 10% w / v in the aqueous phase of the emulsion. Particularly preferred concentrations are from 1 to 5% w / v. The stability of the emulsion can be improved by the addition of one or more coemulsifiers. Suitable pharmaceutically acceptable co-emulsifiers include fatty acids, bile acids and salts thereof. Preferred fatty acids have more than 8 carbon atoms, and particularly preferred is oleic acid. Of the appropriate bile acids, deoxycholic acid is preferred. Suitable preferred salts of the above include the alkali metal salts (for example Na and K). Coemulsifiers may be added at a concentration of 1% w / v or less over the aqueous phase. Buffering agents can also be used in the composition. For example, a damper can be used for 40 maintaining, a pH that is compatible with the nasal fluid, to preserve the stability of the emulsion and / or to ensure that the analgesic component does not pass from the oil phase of the emulsion to the aqueous phase. It will be clear to one skilled in the art that additional components may also be added to the emulsion, including thickening and gelling agents (such as cellulose polymers, particularly sodium carboxymethyl cellulose, alginates, gelanes, pectins, acrylic polymers, agar-agar, gum tragacanth, xanthan gum, hydroxyethyl cellulose, chitosan, as well as polyoxyethylene-polyoxypropylene block copolymers). Also, preservatives such as methyl parabenzoates, benzyl alcohol and chlorobutanol can be added. The release agent may comprise a liposome.

Liposomes are microscopic vesicles comprised of an aqueous component surrounded by a phospholipid bilayer that acts as a permeable capture barrier. Many different kinds of liposomes are known (see Gregoriadis (ed.) In Liposome Technology, 2nd edition, Vol I-III, CRC Press, Boca Ranto, Fia., 1993). Some liposomes can provide a controlled sustained release of the encapsulated drug. In these systems, the rate of drug release is determined by the physicochemical properties of the liposome. Liposomes can be designed for an application 41 specific by modifying the size, composition and surface charge to provide the desired rate of drug release (see Meisner D, et al: In Proceedings, 15th International Symposium on Controlled Relay of Bioactive Materials, 15: 262-263, 1988; M: In Drug Permeation Enhancement, Theory and Application, Hsieh DS (ed.): Marcel Dekker Inc., New York, 1993, pp 171-198, and Meisner D, et al: J Microencapsulation 6: 379-387, 1989) . In this way, the liposome encapsulation can act as an effective and safe release agent in the compositions of the invention. The sustained release property of the liposomal product can be regulated by the nature of the lipid membrane and by the inclusion of other excipients in the composition of the liposomal products. The current liposome technology allows a reasonable prediction of the release rate of the drug based on the composition of the liposome formulation. The rate of release of the drug depends mainly on the nature of the phospholipids, for example hydrogenated (-H) or non-hydrogenated (-G) or the phospholipid / cholesterol ratio (the higher this ratio, the faster the release rate), the hydrophilic / lipophilic properties of the active ingredients and by the liposome manufacturing method. The materials and methods for forming liposomes 42 they are well known to those skilled in the art and include methods of ethanol or ether injection. Typically, the lipid is dissolved in a solvent and the solvent evaporated (often under reduced pressure) to produce a thin film. The film is then hydrated with agitation. The analgesic component is incorporated in the formation stage of the lipid film (if it is lipophilic) or in the hydration phase as part of the aqueous hydration phase (if it is hydrophilic). Depending on the selected hydration conditions and the physicochemical properties of the lipids used, the liposomes may be multilamellar lipid vesicles (VLM), unilamellar lipid vesicles (including small unilamellar vesicles (VUP) and large unilamellar vesicles (VUG)) and multivesicular liposomes. The lipid components typically comprise phospholipids and cholesterol although the excipients may comprise tocopherol, antioxidants, viscosity-inducing agents and / or preservatives. Phospholipids are particularly useful, as those selected from the group consisting of phosphatidylcholines, lysophosphatidylcholines, phosphatidylcerines,. phosphatidylethanolamines, and phosphatidyl inisitol. These phospholipids can be modified using, for example, cholesterols, stearylamines, stearic acid and tocopherols. 43 The compositions of the invention may further comprise other suitable excipients, including for example inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, although corn starch and alginic acid are suitable disintegrating agents. Binders may include starch and gelatin, although the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. Preferably excipients are used as humectants, isotonizing agents, antioxidants, buffers and / or preservatives. The formulation and dosage will depend on whether the analgesic is going to be used in the form of drops or as a spray (aerosol). Alternatively, suspensions such as ointments or gels may be applied to the nasal cavity. However, it is known that the membranes of the nasal mucosa are also capable of tolerating slightly hypertonic solutions. If a suspension or gel is desired in place of a solution, suitable oily vehicles or gels may be used or one or more polymeric materials may be included, which, desirably, are capable of imparting bioadhesive characteristics to the vehicle. 44 Many other * pharmaceutically acceptable nasal vehicles will be evident to those experts. in the technique. The choice of suitable vehicles will depend on the exact nature of the particular nasal dosage form desired, eg, whether the drug to be formulated in a nasal solution (to be used as drops or as a spray) as a nasal suspension, an ointment nasal or a nasal gel. In another embodiment, the nasal dosage forms are solutions, suspensions and gels, which contain a major amount of water (preferably purified water) in addition to the active ingredient. Lesser amounts of other ingredients may also be present as pH adjusters (for example a base such as NaOH), emulsifying or dispersing agents, buffering agents, preservatives, wetting agents and gelling agents (for example methyl cellulose). The nasal compositions of the invention can be isotonic, hypertonic or hypotonic. If desired, sustained-release nasal compositions, for example sustained-release gels, can be prepared easily by cooling, preferably, the desired drug in one of its relatively insoluble forms, such as the free base or an insoluble salt. The composition of the present invention can be adjusted, if necessary, to approximately the same pressure. osmotic that the bodily fluids (ie isotonic). Hypertonic solutions can irritate delicate nasal membranes, while isotonic compositions do not. Isotonicity can be achieved by adding glycerol or an ionic compound to the composition (eg, sodium chloride). The compositions may take the form of a kit of parts, equipment which may comprise the intranasal composition together with instructions for use and / or unit dose containers and / or nasal delivery device. The compositions of the invention allow the buprenorphine or salt or ester thereof to be released or proportioned so that a C of 0 is achieved. 2 ng / ml or more, for example 0. 4 ng / ml or more, within 3 0 minutes (for example within 0.5 to 20 minutes, such as 2 to 15 minutes or 5 to 10 minutes) after introduction into the nasal cavity. The term Cter defines the therapeutic concentration in plasma or interval thereof. Thus, the term is used herein to define the concentration in blood plasma (or range of plasma concentrations) of buprenorphine or salt or ester thereof which produces pain relief or pain reduction. The Cter can be 0. 4 to 5 ng / ml, for example 0. 4 to 1 ng / ml or 0. 5 to 4 ng / ml or 0. 8 to 2 ng / ml. The Tmant is typically at least 2 hours. The term Tmant defines the maintenance duration of Ctez after the 46 administration of the analgesic. For example, the Tmant can be up to 24 hours, up to 12 hours or up to 6 hours, such as 2 to 4 hours or 2 to 3 hours. By means of the invention, therefore, a Cter of 0.4 ng / ml can be achieved within 2 to 15 minutes and be maintained for a period of time Tmant of 2 to 4 hours. As already mentioned, a rapid onset of analgesia and prolonged analgesia can be achieved. The analgesic release profile that can be achieved can avoid the relatively high Cmax values associated with intravenous administration and also lead to an improved therapeutic index. The peak plasma concentration of an analgesic is reached after administration and is defined as Cmax. The invention may allow the reduction or elimination of some or all of the side effects associated with the analgesic. Cmax is typically from 1 to 5 ng / ml, for example from 1 to 4 ng / ml, from 1.5 to 3 ng / ml. Cmax can be 1 to 2 ng / ml, especially for lower doses of buprenorphine. The time at which 0 ^ (Tmax) is reached is typically 10 to 40 minutes after administration, for example 10 to 30 minutes or 15 to 25 minutes, such as 15 to 20 minutes. In preferred embodiments, the release agent is adapted to release the analgesic component so that Cmax = C0pf The term Copt is used in relation to drugs 47 analgesics . that exhibit a dose-response curve to analgesia which is displaced to the left with respect to the dose-response curve for lateral effects. The term defines a therapeutic plasma concentration or range thereof that produces acceptable pain relief or pain reduction but which does not produce side effects or produce side effects which are less than those associated with higher plasma concentrations. The compositions of the invention are administered intranasally to a patient to induce analgesia. An effective amount of buprenorphine or salt or ester thereof may be provided to the patient. As mentioned above, a unit dose can be provided to a window. Alternatively, half a dose or two doses may be provided to each window each time of administration. The dose will depend on the number of factors including the age and sex of the patient, the nature and degree of the pain to be treated and the period of treatment. An adequate dose of buprenorphine or a salt or ester thereof is 0.02 to 1.2 mg, such as 50 to 600 μg or 100 to 400 μg, calculated as buprenorphine. Multiple doses of a composition according to the invention can be employed. For example, the rapid onset of analgesia produced by the solution of the invention may allow autotitulácion of the analgesic by the patient. The analgesic effect of an initial dose can be reliably calibrated or measured quickly by the patient and, if insufficient, can be supplemented immediately by additional doses (often by switching between each window) until the required level of analgesia is reached. Multiple doses can also be used to extend pain relief. For example, 2 to 4 doses per day may be indicated. The composition of the invention can be used to treat an existing pain condition to prevent a pain condition from occurring. An existing pain can be alleviated. The compositions can be used to treat or manage chronic acute pain, for example for the management of post operative pain (for example abdominal surgery, back surgery, cesarean section, hip replacement or knee replacement). Other medical uses have been described above. When in the form of a solution, the compositions according to the invention can be administered to the nasal cavity in forms including drops or aerosols. The preferred method of administration is using a spray device. The spray devices can be single dose (unit) or multiple dose systems, for example comprising a bottle, pump and an actuator. The 49 Suitable spray devices are available from various commercial sources including Pfeiffer, Valois, Bespak and Becton-Dickinson.When in the form of powder or microspheres, a nasal insufflator device may be employed.These devices are already in use for commercial powder systems The insufflator can be used to produce a dispersed, fine column of dry powder or microspheres.The insufflator is preferably provided with means for administering a predetermined dose of the analgesic composition.The powder or microspheres can be contained. in a bottle or container adapted for use with the insufflator Alternatively, the powders or microspheres may be provided in capsules (e.g., gelatin capsules) or other single-dose devices adapted for nasal administration, in which Insufflator modalities may comprise means to break and ablate Go the capsule (or other single-dose device). The following examples illustrate the invention. Example 1; Nasal solution containing buprenorphine (4 mg / ml) and pectin 5 g of pectin were dissolved (SLE DID (trademark) 100, CP Kelco, Denmark) by stirring in approximately 180 ml of water for injection (API) (Baxter, 50 RU). HE. they dissolved 1075 mg of buprenorphine hydrochloride (MacFarlan Smith, UK) and 12.5 g of dextrose (Roquette) in pectin solution. 1.25 ml of phenylethyl alcohol (R.C. Treat, UK) and 50 mg of propyl hydroxybenzoate (Ñipa, RU) were dissolved in the pectin / buprenorphine solution. The solution was adjusted to 250 ml using API. 1M hydrochloric acid (BDH, RU) was added to adjust the pH to 3.6 The final product was a slightly cloudy solution of 4.3 mg / ml buprenorphine hydrochloride (corresponding to 4 mg / ml buprenorphine), 20 mg / ml pectin , 50 mg / ml dextrose, 5 μ? of phenylethyl alcohol and 0.2 mg / ml of propyl hydroxybenzoate. The pH of the solution was 3.6, as mentioned above. The osmolality of the solution was 0.46 osmol / kg. One-dose nasal spray device (Pfeiffer, Germany) was filled with the solution. Each device was filled with 123 μ? of liquid. The drive of the device released a dose of 100 μ? of the liquid containing 400 μg of buprenorphine and 2 mg of pectin. Example 2; Nasal solution containing buprenorphine (2 mg / ml) and pectin. 5 g of pectin were dissolved by shaking. in approximately 180 ml of API. 538 mg of buprenorphine hydrochloride and 12.5 g of dextrose were dissolved in the pectin solution. 1.25 ml of alcohol were dissolved 51 phenylethyl and 50 mg of hydroxybenzoate. of propyl in the pectin / buprenorphine solution. The solution was adjusted to 250 ml using API. The final product is a slightly cloudy solution containing 2.16 mg / ml of buprenorphine hydrochloride (corresponding to 2 mg / ml of buprenorphine), 20 mg / ml of pectin, 50 mg / ml of dextrose, 5 μ / ml of alcohol phenylethyl ether and 0.2 mg / ml propyl hydroxybenzoate. They filled 123 μ? of the above solution in a single-dose nasal spray device Valois Monospray (Pfeiffer, Germany). The drive of the device will release a dose of 100 μ? of the liquid with a content of 200 μg of buprenorphine and 2 mg of pectin. Example 3: Nasal solution containing buprenorphine (4 mg / ml), chitosan and HPMC 0.75 g of HPMC (Methocel (trademark) E4M, Colorcon, UK) was dispersed in approximately 125 ml of pre-heated water for injection (API) (70 -80 ° C) (Baxter, UK). The HPMC dispersion was stirred in an ice bath until a clear solution formed. 1.25 g of chitosan glutamate (Protosan (trademark) UPG213, Pronova, Norway) was dissolved in the HPMC solution. 75 mg of 50% w / w benzalkonium chloride solution (Albright adn Wilson, UK) were dispersed in 10 ml of API and transferred with an additional 40 ml API to a 250 ml volumetric flask. It's 52 transferred 1075 mg of buprenorphine hydrochloride (AcFarlan Smith, UK) and 12.5 g of dextrose (Roquette, UK) to the volumetric flask. The chitosan / HPMC solution and an additional 40 ml API were added to the flask. The solution was adjusted to pH 3.4 using 1M hydrochloric acid solution (BDH, RU) and the contents of the flask was adjusted to 250 ml using API. The final product was a clear colorless solution containing 4.3 mg / ml buprenorphine hydrochloride (corresponding to 4 mg / ml buprenorphine), 5 mg / ml chitosan glutamate, 3 mg / ml HPMC, 50 mg / ml dextrose and 0.15 mg / ml benzalkonium chloride. The osmolality of the final solution was 0.34 osmol / kg and the viscosity, -, as measured using a Brookfield CP70 cone and plate viscometer was 84.7 cps at 2.5 rpm and 25 ° C. One-dose nasal spray devices (Pfeiffer, Germany) were filled with the solution. Each device was filled with 123 μ? of liquid. The drive of the device released a dose of 100 μ? of liquid containing 400 μg of buprenorphine, 0.5 mg of chitosan and 0.3 mg of HPMC. Consequently, a dose of 400 μg of buprenorphine is provided by a single spray in a window. A dose of 800 μ9 is provided by a single spray in each window. 53 Example 4; Nasal solution containing buprenorphine (1 mg / ml), chitosan and HPMC A solution containing HPMC, chitosan glutamate and benzalkonium chloride was prepared according to Example 3. 269 mg of buprenorphine hydrochloride and 12.5 g of mannitol were transferred ( Sigma, UK) to the volumetric flask. The chitosan / HPMC solution and an additional 40 ml API were added to the flask. The pH of the solution is adjusted to pH 3.6 using a 1M hydrochloric acid solution and the contents of the flask adjusted to 250 ml using API. The final product is a clear colorless solution containing 1.08 mg / ml buprenorphine hydrochloride (corresponding to 1 mg / ml buprenorphine), 5 mg / ml chitosan glutamate, 3 mg / ml HPMC, 50 mg / ml Mannitol and 0.15 mg / ml benzalkonium chloride. They filled 123 μ? of the above solution in a single dose nasal spray device (Pfeiffer, Germany). The drive of the device releases a dose of 100μ? of liquid with a content of 100 μg of buprenorphine, 0.5 mg of chitosan and 0.3 mg of HPMC. 5 ml of the solution are filled in a 10 ml glass bottle. A 100 μ? Pump is connected? Valois VP7 and an actuator (Valois, France) to the bottle. When primed, the pump will dispense 100 μ? of a solution with a content of 100 μg of buprenorphine. 54 Example .5; Nasal solution containing buprenorphine (4 mg / ml), chitosan and poloxamer 25 g of poloxamer (Lutrol (trademark) F-68, BASF, Germany) were dissolved by shaking in 100 ml of water for injection (API) (Baxter, UK ) at a temperature of 2 to 8o. 1.25 g of chitosan glutamate (Protasan (trademark) UPG213, Pronova, Norway) was dissolved in the poloxamer solution. 75 mg of 50% w / w benzalkonium chloride solution (Albright and Wilson, UK) were dispersed in 10 ml of API and transferred with an additional 40 ml of API to a 250 ml volumetric flask. 1075 mg of buprenorphine hydrochloride (MacFarlan Smith, UK) and 12.5 g of dextrose (Roquette, UK) were transferred to the volumetric flask. The chitosan / poloxamer solution and an additional 40 ml of API were added to the flask. The solution was adjusted to pH 3.4 using 1M hydrochloric acid solution (BDH, RU) and the contents of the flask was adjusted to 250 ml using API. The final product was a clear colorless solution containing 4.3 mg / ml buprenorphine hydrochloride (corresponding to 4 mg / ml buprenorphine), 5 mg / ml chitosan glutamate, 100 mg / ml poloxamer 188, 50 mg / ml of dextrose and 0.15 mg / ml of benzalkonium chloride. The osmolality of the final solution was 0.60 Osmol / kg. One-dose nasal spray devices (Pfeiffer, Germany) were filled with the solution. Each device 55 was filled with 123 μ? of the liquid. The drive of the device released a dose of 100 μ? of the liquid containing 400 μ9 of buprenorphine, 0.5 mg of chitosan and 10 mg of poloxamer 188. Example 6: Nasal solution containing buprenorphine (1 mg / ml), chitosan and poloxamer A solution containing chitosan glutamate, poloxamer 188 was prepared and benzalkonium chloride according to Example 5. 269 mg of buprenorphine hydrochloride and 12.5 g of mannitol (Sigma, UK) were transferred to the volumetric flask. HE. they added the chitosan / poloxamer solution and an additional 40 mi API to the flask. The pH of the solution was adjusted to pH 3.6 using 1M hydrochloric acid and the contents of the flask were adjusted to 250 ml using API. The final product is a clear colorless solution containing 1.08 mg / ml buprenorphine hydrochloride (corresponding to 1 mg / ml buprenorphine), 5 mg / ml chitosan glutamate, 100 mg / ml poloxamer 188, 50 mg / ml of mannitol and 0.15 mg / ml of benzalkonium chloride. They filled 123 μ? of the above solution in a single dose nasal spray device (Pfeiffer, Germany). The drive of the device will release a dose of 100 μ? of liquid containing 100 μg of buprenorphine, 0.5 mg of chitosan and 10 mg of poloxamer 188. 4 ml of solution were filled in a glass bottle 56 of 5 mi. A 100 μ nasal spray pump was connected? of Pfeiffer and an actuator to the bottle. When primed, the pump will dispense 100 μ? of solution with a content of 100 μ? of buprenorphine. Example 7: Effects of the different parameters of buprenorphine-pectin solutions General methods Appearance, pH (Mettler MP230 pH) and osmolality (Osmomat 030 cryoscopic osmometer) of the solutions were determined. The viscosity of the solution was, measured using a Cone Rheometer and Brookfield plate. The results given are the average of determinations at three rotation speeds appropriate for the viscosity of the solution. The spray characteristics of the multi-dose nasal spray device (standard nozzle, 0.1 ml pump, Cat. No. 62897) were evaluated by measuring the angle of the column using image analysis. The given results are the average of four determinations (two to one orientation and two to a rotation of 90 ° with respect to the first orientation). The buprenorphine content of the formulations was determined by CLAP. The gels were prepared by mixing 20 ml of the formulation in a controlled manner with 5 ml of 57-chloride solution. standard calcium (9.44 mg / ml CaCl2.2H20). before putting it to rest for 1 hour at room temperature. A visual evaluation of the writing, uniformity, clarity and evidence of syneresis of each gel was conducted and, in addition, the structure of the gel was examined with a Texture Analyzer of Stable Microsystems (from single determinations) expressed in terms of force ( maximum penetration force) and area (total gel penetration work). Effect of concentration, pectin on appearance, properties of the solution / gel and dew characteristics 1. Methods Buprenorphine hydrochloride (107.5 mg) and anhydrous dextrose (1.25 g) were stirred in 18-20 ml of water in a flask volumetric 25 ml together with an appropriate amount of pectin and the mixture was stirred overnight or until a solution formed. The mixture was then brought to 25 ml with water to give a solution containing 4 mg / ml of buprenorphine, 50 mg / ml of dextrose and 1, 5, 10, 20, 30, 40 or 80 mg / ml of pectin and They determined pH, appearance, osmolality, viscosity. In addition, the spray characteristics of a Pfeiffer multi-dose nasal spray device (standard nozzle, 0.1 ml pump No. Cat. 62897) were evaluated by measuring the angle of the column using image analysis. The gels were prepared by controlled mixing of 20 ml of formulation with 5 ml of 58 solution, of standard calcium chloride (9.44 mg / ml of CaCl2.2H20) before resting for 1 hour at room temperature A visual evaluation of the writing, uniformity, clarity and evidence of syneresis of each gel was conducted, In addition, the structure of the gel was examined with a Stable Microsystems Texture Analyzer, using an in vi tro method to simulate the gelation that can occur when the pectin formulation comes in contact with the surface of the nasal mucosa. addition of 2 ml of each formulation to an equal volume of simulated nasal electrolyte solution (SNES) (comprised of 8.77 g / l of sodium chloride, 2.98 g / l of potassium chloride and 0.59 g / l of calcium chloride dihydrate ) and shaking gently The mixtures were allowed to stand for 1 hour at room temperature before the visual evaluation 2. Results As the concentration of pectin increases, the solutions become more and more If the turbidity is increased, the osmolality and viscosity increase and the angle of the column decreases (Table 1). It had an excellent relationship between the concentration and the angle of the column of up to 30 mg / ml of pectin. The pH was not significantly affected by the pectin concentration. After the addition of calcium ions the formed pectin gels visually satisfactorily in the concentration range of 5-20 mg / ml (Table 2). Correspondingly, greater integrity in the structure of the gel was noted over this range. Higher concentrations of pectin that resulted from the texture analysis were conclusive because the homogeneity of the gel is difficult to control and an increase in syneresis was observed. At a lower calcium ion concentration (SNES) the pectin produced mobile gels at 10-20 mg / ml and strong non-homogeneous gels, at higher concentrations. Table 1: Appearance characteristics, pH, osmolality, viscosity and roclo (angle of the pen) of buprenorphine solutions containing .3 mg / ml buprenorphine hydrochloride (BPN.HC1), 50 mg / ml dextrose and different concentrations of pectin (Slendid 100). * 60 Table 2. Geling properties of buprenorphine solutions containing 4.3 mg / ml of BPN.HCl, 50 mg / ml of dextrose and different concentrations of pectin (Slendid 100) when mixed with standard calcium chloride solution.

Table 2a. Geling properties of buprenorphine solutions containing 4.3 mg / ml BPN.HCl, 50 mg / ml dextrose and different concentrations of pectin (Slendid 100) when mixed with SNES. Lot No. Pectin Conc. Visual evaluation (mg / ml) 161 1 Solution will give, slightly vBr jsa, .xx3lora NlogelifioD. 162 5 Solution will give, vecosa, irco ra Nogeíficó. 163 10 Gel daro, colorless, diffusion should. 164 20 Peeling yellow gel, semitransparent, of d-ustóndebl 165 30 Gel amarto pallet semirransD 166 40 Gel amarita páSdo serrtrransparente, with something effe syneresis. 167 80 GeJarrenlb pale opaque, rr ^ 61 Effect of H on the properties. of solubility and gelling of buprenorphine hydrochloride 1. Methods Standard solutions were prepared containing pectin (Slendid 100) (20 mg / ml) and dextrose (50 mg / ml) at various pH in the range of pH 3.0 to 6.0 (the adjustments of pH were made with 0.1 M HC1 or 0.1 M meglumine). An excess of buprenorphine hydrochloride was then stirred overnight at 18 ° C in 5 or 25 ml of each solution. The saturated solutions were recovered by passing each mixture through a 0.2 μp polycarbonate membrane filter. The concentration of buprenorphine hydrochloride in the filtrate was determined by CLAP. In preliminary experiments it was found that the addition of an excess of buprenorphine hydrochloride reduces the pH of the solutions (not buffered). To produce solutions in the upper end of the desired pH range, a minimum excess of buprenorphine hydrochloride was added to the solutions (5 ml) - containing pectin (Slendid 100) (20 mg / ml) and dextrose (50 mg / ml) ) adjusted to several pH values in the range of pH 4.5 to 6.0 with 0.1M HCl or 0.1M meglumine. The excess amount of buprenorphine hydrochloride added was based on preliminary findings and on the solubility data reported by buprenorphine hydrochloride (Cassidy et al, J. Controlled Relay 25, 21-29, 1993). 62 After stirring overnight at 18 ° C ,. the mixtures were examined to confirm that the undissolved drug remained before the saturated solutions were recovered by passing each mixture through a 0.2 μt polycarbonate membrane filter? For the selected formulations, gels were prepared by controlled mixing in 20 ml of formulation with 5 ml of standard calcium chloride solution (9.44 mg / ml of CaCl2.2H20) before allowing to stand for one hour at room temperature. There was a visual evaluation of the structure, uniformity, clarity and syneresis evidence of each gel, in addition, the structure of the gel was examined with the Texture Analyzer of Stable Microsystems. 2. Results Buprenorphine was sparingly soluble (more than 10 mg / ml) in aqueous solutions containing 20 mg / ml pectin + 50 mg / ml dextrose at a pH lower than 4.4 (Table 3). In general, the solubility falls as the pH increases above 4.5 (Table 3a). The solutions were slightly soluble (less than 10 mg / ml) at pH 4.5-6.0. The gelation properties were not affected to a large extent by the pH (and therefore by the concentration of buprenorphine) (Table 4). 63 Table 3 .. Solubility of BPN.HC1 at pH 3.2-4.0 in solutions containing 20 mg / ml pectin (Slendid 100) and 50 mg / ml dextrose.

* Expressed as buprenorphine-free base Table 3a. Solubility of BPN.HC1 at pH 4.4-5.3 in solutions containing 20 mg / ml pectin (Slendid 100) and 50 mg / ml dextrose.

* Expressed as buprenorphine-free base 64 Table 4, Effect of p'H on the gelifcation properties of BPN.HC1 in solutions containing 20 mg / ml of pectin (Slendid 100) and 50 mg / ml of dextrose when mixed with standard calcium chloride solution.

* Small volumes were used (14 ml of formulation and 3.5 ml of CaCl2.2H20) due to the volume loss higher than expected during the filtration. Effect of osmolality (concentration of dextrose or mannitol) on the viscosity, dew characteristics and gelling properties of buprenorphine hydrochloride. 2. Methods Buprenorphine hydrochloride (107.5 mg) and pectin (Slendid 100) (500 mg) in 18-20 ml of water were stirred in a 25 ml volumetric flask together with an appropriate amount of anhydrous dextrose or mannitol and the mixture was stirred. it stirred overnight until the solution formed. The solution was then brought to 25 ml with water to give a solution containing 4 mg / ml of buprenorphine, 20 mg / ml of pectin and 15, 50, 87, 122, 157 or 1925 65 mg / ml dextrose (or "15, 50, 87, 122 mg / ml mannitol) and the pH, appearance, osmolality, viscosity were determined.Also, the spray characteristics of the Pfeiffer multi-dose nasal spray device were evaluated. (Standard nozzle, 0.1-ral pump, Catalog No. 62897) by measuring the angle of the column using image analysis The genes were prepared by controlled mixing of 20 ml of formulation with 5 ml of standard calcium chloride solution ( 9.44 mg / ml of CaCl2.2H20) before allowing to stand for 1 hour at room temperature, a visual evaluation of the structure, or uniformity, clarity and evidence of syneresis of each gel was conducted and in addition, the structure of the gel was examined with a Texture Analyzer of Stable icrosystems 2. Results As the dextrose concentration increased from 15 to 50 mg / ml the spray characteristics of a nasal spray device were affected according to the indications r a decrease in column angle associated with an increase in viscosity: a narrow column was consistently obtained above 50 mg / ml dextrose (Table 5). As the mannitol concentration was increased there was a slight increase in viscosity and a slight decrease in the angle of the column (Table 6). The structure of the gel may have weakened slightly as the dextrose concentration increased. This 66 was indicated, by a visual evaluation but the results of the texture analysis were inconclusive (Table 7). The structure of the gel was affected at a higher concentration of mannitol. Visual evaluation and texture analysis indicated that less uniform and weaker gels were produced (Table 8). Table 5. Osmolality, viscosity and spray characteristics of the 4.3 mg / ml solution of BPN.HCl 20 mg / ml pectin (Slendid 100) containing various concentrations of dextrose.

Table 6. Osmolality, viscosity and dew characteristics of the 4.3 mg / ml solution of BPN.HCl 20 mg / ml pectin (Slendid 100) containing several concentrations of mannitol.

* Does not dissolve 67 Table 7, Gelation properties of the 4.3 mg / ml solution of BPN.HCl / 20 mg / ml pectin (Slendid 100) containing various concentrations of dextrose Table 8. Gelation property of 4.3 mg / ml solution of BPN.HCl / 20 mg / ml pectin (Slendid 100) containing various concentrations of mannitol when mixed with a standard calcium chloride solution.

Lot OsmotaOdad Texture analysis Visual evaluation No. (ósmol / kg) Strength (g) Area (gs) 120 0.16 477 9006 Strong, uniform gel, amanto páítío, serrirtransparente, with some syneresis. 121 0.37 497 8991 Heavy, uniform gel, pale, semitransparent amanto, with some syneresis. 122 0.61 358 7160 Gel déri, non-uniform, yellow pakb, serniransparent, with some syneresis. 123 0.85 221 3881 Gel zebu, not uniform, pale yellow, semi-transparent, with some syneresis. 68 Effect of the concentration of dextrose and mannitol on the solubility of buprenorphine 1. Methods Pectin solutions containing (Slendid 100) (20 mg / ml) were prepared at pH 3, 4, 5 and 6 (pH adjustments were made with 0.1M HC1 or 0.1M meglumine). In 5 ml of each solution, 0, 62.5, 125, 187.5 or 200 mg of anhydrous dextrose or mannitol was dissolved to give approximate dextrose / mannitol concentrations of 0, 12.5, 25, 37.5 or 50 mg / ml, respectively. Then an excess of buprenorphine hydrochloride was added and the mixture was stirred overnight at 18 ° C. Saturated solutions of buprenorphine hydrochloride were produced by passing the mixture through a 0.2 μp polycarbonate membrane filter. The concentration of buprenorphine hydrochloride in the filtrate was determined by CLAP. 2. Results The solubility of buprenorphine in aqueous solutions containing 20 mg / ml of pectin was not significantly affected by concentration of dextrose (Table 9) or mannitol (Table 10) through the pH measurement range. 69 Table 9 .. Effect of dextrose concentration on the solubility of BNP.HCl in the solution containing 21 mg / ml of pectin (Slendid 100).

* Expressed as buprenorphine-free base 70 Table 10. Effect of mannitol concentration on the solubility of BPN.HC1 in solution containing 20 mg / ml of pectin (Slendid 100) Expressed as free base of buprenorphine 71 Control experiment; Effect of mixing pectin AM solution (high in methoxy) (20 mg / ml pectin [citric] Genu (trademark) type ÜSP-H) with calcium Pectins suitable for retaining drugs on mucous surfaces have a low degree of esterification (also called "low methoxy" or "BM" pectins) and, in aqueous solution, they will gel in the presence of the ions found in mucous fluid, especially divalent ions, in particular calcium. As a negative control, a "high methoxy" pectin solution was prepared and mixed with a solution containing calcium ions. 1. Methods Buprenorphine hydrochloride (107.5 mg), anhydrous dextrose (1.25 g) and pectin (pectin [citric] Genu type USP-H, CP Kelco, Lille Skenved, Denmark) were stirred (500 mg) in 18-20 ml of Water in a volumetric flask in 25 ml overnight or until a solution is formed. The mixture was then brought to 25 ml with water to give a solution containing 4 mg / ml buprenorphine, 20 mg / ml pectin and 50 mg / ml dextrose and determined pH and osmolality. A 20 ml aliquot of the formulation (under controlled conditions) was mixed with 5 ml of standard calcium chloride solution (9.44 mg / ml CaCl2.2H20) before allowing to stand for 1 hour at room temperature. Then the uniformity of the structure and clarity of the product were evaluated. 72 2. Results The solution had a pH of 3.3 and an osmolality of 0.35 osmol / kg. An opaque, pale yellow solution was formed when the solution was mixed with 9.44 mg / ml of CaCl2.2H20. The solution did not gel yet when left for 1 hour at room temperature. Example 8; Clinical Study Unit doses of intranasal buprenorphine formulations of examples 1, 3 and 5 (formulations A to C) and a commercial intravenous formulation of buprenorphine (trademark Temgesic; Formulation D) were administered to healthy human volunteers. The unit doses administered to the volunteers were the following: - 800 μg of buprenorphine hydrochloride, calculated as buprenorphine, of formulations A, B or C administered intranasally; and - a single slow intravenous injection of 400 μg of buprenorphine hydrochloride, calculated as buprenorphine, of formulation D. The dosage was made to 12 healthy volunteers using a randomized, completely cross-over design. Each dose was separated by at least 7 days. Volunteers were required to inject during the night before dosing. The subjects were admitted to a clinic the night before the administration of the dose and remained in the clinic until 73 the collection of blood samples for each day of study. Blood samples were collected at regular intervals up to 24 hours after each dose administration. The volunteers were released from the clinic after completing all the study procedures for 24 hours. There was an elimination period of at least 7 days before each dose. The pharmacokinetics of each dose regimen were evaluated. The results are shown in Figures 1 to 3. These intranasal solutions showed similar pharmacokinetic profiles. The Cter was reached within 5 to 10 minutes for each formulation and the Cmax was reached in 20 minutes or less. The data indicated that the initial plasma peak was shortened for intranasal formulations compared to intravenous administration. That seemed more pronounced in formulation A. The three intranasal solutions gave a high bioavailability (Table 11) . Table 11. Comparison of the key pharmacokinetic parameters derived from clinical studies on intranasal buprenorphine with published data on the sublingual tablet and with a formulation of buprenorphine dextrose. Parameter FC l-katnstfeestJ iosc-r-cosdebLprenortra (antenur technique) (anterior) intranasal bc ^ aenoffirasiiángLial intranasal bt-prenornna 0.8mgde OSmgde OBmgde Tablet TabletO8 03mgderducon pedna pectr HPMC qLitosarY 0.4mg mg dextrose pobxamer C ngM) 3.7 4.4 3? 05 1.04 1B? ™, (? t?) 20 18 20 210 1S2 31 Báspcntity 80% 81% 72% 56% 48% 74 A "pharmacokinetic profile for an intranasal dose of 400 μ9 of formulation A, calculated as buprenorphine, was calculated from the data for the 800 μ9 dose for formulation A. This profile is shown in Figure 4. Figure 4 also shows the pharmacokinetic profile for the 400 <3 dose of Formulation A which was administered intravenously It is noted that in relation to this date, the best method known to the applicant to carry out the said invention is that it is clear from the present description of the invention.

Claims (46)

1. 75 CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. An aqueous solution suitable for intranasal administration, characterized in that it comprises from 0.1 to 10 mg / ml of buprenorphine or a physiologically acceptable salt or ester thereof. and from 5 to 40 mg / ml of a pectin having an esterification degree of less than 50%; solution which has a pH of from 3 to 4.2, is substantially free of divalent metal ions and gels on the nasal mucosa. 2. The solution according to claim 1, characterized in that the buprenorphine or buprenorphine salt or ester is present in an amount of 0.5 to 8 mg / ml. 3. The solution according to claim 2, characterized in that the buprenorphine or buprenorphine salt or ester is present in an amount of 1 to 6 mg / ml calculated as buprenorphine. 4. The solution according to any of the preceding claims, characterized in that it comprises buprenorphine hydrochloride. 5. The solution according to any of the preceding claims, characterized in that the pectin is present in an amount of 10 to 30 mg / ml. 76 6. . The solution according to any of the preceding claims, characterized in that the pectin has an esterification degree of 10 to 35%. 7. The solution according to any of the preceding claims, characterized in that the pH is 3. 5 to 4.0. 8. The solution according to any of the preceding claims, characterized in that the pH has been adjusted by means of hydrochloric acid. 9. The solution according to any of the preceding claims, characterized in that it comprises a preservative. 10. The solution according to claim 9, characterized in that it comprises phenyl ethyl alcohol and propyl hydroxybenzoate as preservatives. 11. The solution according to any of the preceding claims, characterized in that it has an osmolality of 0.35 to 0.5 osmol / kg. The solution according to any of the preceding claims, characterized in that it contains dextrose as an agent for adjusting the tonicity. 13. An aqueous solution suitable for intranasal administration, characterized in that it has a pH of 3.5 to 4.0, which is substantially free of divalent metal ions and which comprises: (a) from 1 to 6 mg '/ ml of buprenorphine or a physiologically acceptable salt or ester thereof, calculated as buprenorphine; (b) from 10 to 40 mg / ml of a pectin having an esterification degree of 10 to 35%, and (c) dextrose as an agent for adjusting the tonicity. 14. A process for preparing an aqueous solution according to claim 1, characterized in that it comprises dissolving buprenorphine or a physiologically acceptable salt or ester thereof in water; mixing the resulting solution with a water solution of a pectin having an esterification degree of less than 50%, so that the mixed solution comprises 0.1 to 10 mg / ml of buprenorphine or the salt or ester thereof and of 5 to 40 mg / ml of pectin; and adjust the pH of the solution to a value of 3 to 4.2 if desired. 15. The process according to claim 14, characterized in that the resulting solution is introduced into a nasal delivery device. 16. An aqueous solution suitable for intranasal administration, characterized in that it comprises: (a) from 0.1 to 10 mg / ml of buprenorphine or a physiologically acceptable salt or ester thereof; (b) from 0.1 to 20 mg / ml of chitosan, and (c) from 0.1 to 15 mg / ml of hydroxypropylmethylcellulose; 78 solution. which has a pH of 3 to 4.8 17. The solution according to claim 16, characterized in that the hydroxypropylmethylcellulose has an apparent viscosity of 3000 to 6000 cps and is present in an amount of 0.1 to 15 mg / ml. The solution according to claim 17, characterized in that the hydroxypropylmethylcellulose is present in an amount of 0.5 to 10 mg / ml. 19. An aqueous solution suitable for intranasal administration, characterized in that it comprises: (a) from 0.1 to 10 mg / ml of buprenorphine or a physiologically acceptable salt or ester thereof, (b) from 0.1 to 20 mg / ml of a chitosan, and (c) from 50 to 200 mg / ml of a polyoxyethylene-polyoxypropylene copolymer of the general formula HO (C2H40) a (C3H60) b (C2H40) aH where a is from 2 to 130 and b is from 15 to 67; solution which has a pH of 3 to 4.8. 20. The solution according to claim 19, characterized in that the polyoxyethylene-polyoxypropylene copolymer is present in an amount of 80 to 120 mg / ml. 21. The solution according to claim 19 or 20, characterized in that the polyoxyethylene-polyoxypropylene copolymer has a molecular weight of 7,000 to 15,000. 79 22. The solution according to any of claims 19 to 21, characterized in that the polyoxyethylene-polyoxypropylene copolymer is one in which a is 80 and b is 27. 23. The solution according to any of claims 16 to 22, characterized in that it has an osmolality of 0.32 to 0.4 osmol / kg. The solution according to any of claims 16 to 23, characterized in that the buprenorphine or buprenorphine salt or ester is present in an amount of 0.5 to 8 mg / ml.- 25. The solution according to claim 24, characterized in that the buprenorphine or buprenorphine salt or ester is present in an amount of 1 to 6 mg / ml calculated as buprenorphine. 26. The solution according to any of claims 16 to 25, characterized in that it comprises buprenorphine hydrochloride. 27. The solution according to any of claims 16 to 26, characterized in that the chitosan is present in an amount of 2 to 10 mg / ml. 28. The solution according to any of claims 16 to 27, characterized in that the chitosan is a physiologically acceptable salt of a deacetylated chitin. 80 29. The solution according to claim 28, characterized in that the salt is chitosan glutamate. 30. The solution according to any of claims 16 to 29, characterized in that the pH is 3.5 to 4.0. 31. The solution according to any of claims 16 to 30, characterized in that the pH has been adjusted by means of hydrochloric acid. 32. The solution according to any of claims 16 to 31, characterized in that it comprises a preservative. 33. The solution according to claim 32, characterized in that the preservative is benzalkonium chloride. 34. The solution according to any of claims 16 to 33, characterized in that it contains dextrose as an agent for tonicity adjustment. 35. A process for the preparation of an aqueous solution according to claim 16, characterized in that it comprises dissolving buprenorphine or a physiologically acceptable salt or ester thereof, a chitosan and hydroxypropylmethylcellulose in water to provide a solution comprising from 0.1 to 10. mg / ml of buprenorphine or the salt or ester thereof, from 0.1 to 20 mg / ml of chitosan and from 0.1 to 15 mg / ml of hydroxypropylmethylcellulose; and adjust the pH 81 of the solution to a value of 3 to 4.8 as desired. 36. A process for the preparation of an aqueous solution according to claim 19, characterized in that it comprises dissolving buprenorphine or a physiologically acceptable salt or ester thereof, a chitosan and a polyoxyethylene-polyoxypropylene copolymer of the general formula HO (C2H40 ) a (C3HsO) b (C2H40) aH where a is from 2 to 130 and b is from 15 to 67 in water to provide a solution comprising 0.1 to 10 mg / ml of buprenorphine or the salt or ester thereof, of 0.1 at 20 mg / ml of chitosan and 50 to 200 mg / ml of the polyoxyethylene-polyoxypropylene copolymer; and adjust the pH of the solution to a value of 3 to 4.8 as desired. 37. The process according to claim 35 or 36, characterized in that the resulting solution is introduced into a nasal delivery device. 38. A nasal delivery device characterized in that it is loaded with a solution according to any of claims 1 to 13 or 16 to 34. 39. The device according to claim 38, characterized in that it is a spray device. 40. The use of a solution according to any of claims 1 to 13 or 16 to 34 for the manufacture of a nasal delivery device for use to induce analgesia. 41. A method to induce analgesia in a patient who need .del. same, characterized in that it comprises administering intranasally an aqueous solution according to claim 1, 16 or 19 to the patient. 42. The use of buprenorphine or a salt or ester thereof physiologically acceptable and a release agent for the manufacture of a medicament for intranasal administration of treatment for average pain of which, upon introduction into the nasal cavity of a patient to be When treated, the buprenorphine or salt or ester thereof is brought to the bloodstream to produce within 30 minutes a therapeutic plasma concentration of 0.4 ng / ml or higher which is maintained for a Tmant time of at least 2 hours. 43. The use according to claim 42, wherein the medicament is an aqueous solution. 44. The use according to claim 42 or 43, wherein the release agent is a pectin having an esterification degree of 10 to 35%. 45. The use according to any of claims 42 or 44, wherein Cter is 0.4 to 1 ng / ml and is produced within 1 to 15 minutes. 46. The use according to any of claims 42 or 45, wherein Craax is from 1 to 5 ng / ml and is reached from 10 to 30 minutes after the introduction of the drug into the nasal cavity of a patient to be treated. 83 Al. The use of "a pharmaceutical composition which comprises buprenorphine or a physiologically acceptable salt or ester thereof and a release agent for the manufacture of a nasal delivery device to be used to induce analgesia with which, upon introduction into the nasal cavity of a patient to be treated, the buprenorphine or salt or ester thereof is taken to the bloodstream to produce within 30 minutes a therapeutic concentration in Cter plasma of 0.2 ng / ml or greater which is maintained during a Tmant time of at least 2 hours 48. A pharmaceutical composition suitable for use as an analgesic, characterized in that it comprises buprenorphine or a physiologically acceptable salt or ester thereof and a release agent whereby, after introduction into the nasal cavity of a patient to be treated, the buprenorphine or salt or ester thereof is taken to the bloodstream to produce within 30 minutes a at a therapeutic plasma concentration C er of 0.2 ng / ml or greater which is maintained for a Tmant time of at least 2 hours. 49. A method for inducing analgesia in a patient in need thereof, characterized in that the method comprises intranasally administering to the patient a pharmaceutical composition which comprises buprenorphine or a physiologically acceptable salt or ester thereof and an agent of release so that, after introduction into the nasal cavity of the patient to be treated, the buprenorphine or salt or ester thereof is brought to the bloodstream to produce within 30 minutes a CCER plasma therapeutic concentration of 0.2 ng / ml or greater which is maintained for a Tmant time of at least 2 hours. 50. The method according to claim 49, characterized in that a unit dose of 0.1 to 0.6 mg of buprenorphine or buprenorphine salt or ester, calculated as buprenorphine, is administered intranasally.